1. Field of the Invention
Aspects of the disclosed invention relate to a method of application and use of adipose tissue derived stem cells for the treatment of mammalian uterine disorders including fertility and pregnancy related disorders, particularly endometriosis.
2. Description of the Related Art
Healthy and undamaged uterine cavity and endometrial lining are essential in order to conceive and maintain a full term pregnancy. There are various conditions related to the uterine cavity or the lining that can cause or contribute to reproductive problems such as infertility or recurrent miscarriage. Such conditions include endometriosis, poor endometrium or a thin uterine lining, uterine polyps and fibroids, intrauterine adhesions and uterine cavity scar tissue.
The implantation phase of the mammalian embryo requires a delicate interchange between the embryo and its mother. For this phase to be successful a receptive and healthy endometrium is required (Giudice L C (1999) Potential biochemical markers of uterine receptivity. Hum Reprod 14(Suppl),3-16). Reduced endometrial receptiveness is found in a growing number of unexplained infertilities (Lessey B A, Castelbaum A J, Sawin S W and Sun J (1995) Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril 63,535-542). Therefore, an inadequate endometrium can be considered as a main fertility-determining factor.
Although knowledge on molecular mechanisms in the endometrium has increased tremendously, translation of this basic research into daily clinical routine is rather limited. Moreover, endometriosis is an extremely common condition, which affects approximately 15% of women in their reproductive years. It is a condition wherein the endometrium is found in ectopic locations outside the uterus. Such misplaced tissue may implant on the ovaries, uterus, bowel, bladder utero-sacral ligaments, or peritoneum. It is a degenerative disease of uterine glands and surrounding stroma that leads to infertility (Kenney R M. The etiology, diagnosis and classification of chronic degenerative endometritis. Equine Vet J 1992; 25:186, Schoon H A, Schoon D, Klug E. Uterusbiopsien als Hilfsmittel f{dot over ( )}ur Diagnose and Prognose von Fertilit{umlaut over ( )}atsst{umlaut over ( )}orungen der Stute. Pferdeheilkunde 1992; 8:355-362). Uterine glands secretions are considered essential to embryo implantation, fetal development and survival. Presently, endometrosis is defined as an active or inactive periglandular and/or stromal endometrial fibrosis including glandular alterations within fibrotic foci. Single glands and/or glandular nests can be affected (Kenney R M. Cyclic and pathologic changes of the mare endometrium as detected by biopsy, with a note on early embryonic death. J Am Vet Med Assoc 1978; 172:241-262).
The expression pattern of selected endometrial proteins, such as steroid hormone receptors, protein of proliferation intensity (Ki-67-antigen), the filaments vimentin, desmin, α-smooth muscle actin (α-actin), laminin and others have been studied (Walter I, Handler J, Reifinger M, Aurich C. Association of endometrosis in horses with differentiation of periglandular myofibroblasts and changes of extracellular matrix proteins. Reproduction 2001; 121:581-586, Hoffmann C, Ellenberger C, Mattos R C, Aupperle H, Dhein S, Stief B, Schoon H A. The equine endometrosis: new insights into the pathogenesis. Anim Reprod Sci 2009; 111:261-278).
These studies demonstrated that the affected endometrium seems unable to provide an appropriate environment for the correct expression of these proteins, when compared with healthy endometrium. However, until now, the etiology of endometrosis is not defined and no effective treatment is available.
Mesenchymal stem cells (MSCs) can be isolated from different adult tissues among which bone marrow and adipose tissue are more commonly used. These cells have the capacity to differentiate into several tissues of mesoderm and ectoderm origin, including bone, cartilage, tendon, muscle, adipose and neurons.
MSCs secret a diverse set of bioactive molecules, which are immunomodulatory (Aggarwal S, Pittenger M F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815-1822. Uccelli A, Prockop D J. Why should mesenchymal stem cells (MSCs) cure autoimmune diseases? Curr. Opin. Immunol. 2010; 22:768-774).
Other molecules released by MSCs provide regeneration and remodeling of injured tissue, through their trophic activities (Diekman et al., Chondrogenesis of adult stem cells from adipose tissue and bone marrow: induction by growth factors and cartilage-derived matrix. Tissue Eng Part A. 2010 February; 16(2):523-33, Caplan A I, Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011; 1:11-15), which involve inhibition of apoptosis, stimulation of MSC-mediated angiogenesis by secretion of VEGF, as well as anti-scar formation activity (Sorrell J M, Baber M A, Caplan A I. Influence of adult mesenchymal stem cells on in vitro vascular formation. Tissue Eng Part A 2009; 15:1751-1761). Finally, MSCs secreted mitogens, which stimulate tissue-intrinsic progenitors to divide and appropriately differentiate (Wagner J, Kean T, Young R, Dennis J E, Caplan A I. Optimizing mesenchymal stem cell-based therapeutics. Curr Opin Biotechnol 2009; 20:531-536, Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove C J, Bovenkerk J E, Pell C L, Johnstone B H, Considine R V, March K L. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109:1292-1298).
Endometrosis is an age-associated, degenerative alteration of uterine glands and surrounding stroma, directly related to fertility problems. Because of the therapeutic properties MSCs, they have potential for treatment of this disease. Success of stem cell therapies depends at least, in part, on cell delivery, which should ensure wide cell distribution and homing within the injured site (Sorrell J M, Baber M A, Caplan A I. Influence of adult mesenchymal stem cells on in vitro vascular formation. Tissue Eng Part A 2009; 15:1751-1761).
To substitute for damaged cells and aiming at upgrading tissue integrity and function, a cell suspension is injected into the damaged tissue or into the blood circulation.
Depending on the pathology, treatment strategies can differ considerably (Wagner J, Kean T, Young R, Dennis J E, Caplan A I. Optimizing mesenchymal stem cell-based therapeutics. Curr Opin Biotechnol 2009; 20:531-536). A need exist for a method and therapy to treat and reduce the systems of these uterine disorders.